During early HIV infection, the virus stably integrates in long-lived cellular reservoirs which persist despite continuous antiretroviral therapy (ART). ART initiation during early acute HIV infection may limit viral reservoir size, reduce immune activation and improve treatment outcomes and post-treatment virologic control in adults and children. There are scant data on reservoir dynamics and determinants from sub Saharan Africa, the region of the world with most global pediatric HIV. We have previously demonstrated influence of antibody- dependent cellular cytotoxicity (ADCC) on infant HIV acquisition and disease control. We have also demonstrated marked plasticity of the natural killer (NK) cell population over the course of infancy and NK suppression of HIV and acquisition in adult cohorts. It is plausible that these immune responses may influence reservoir establishment and decay. Understanding these determinants could inform vaccine or therapeutic strategies to accelerate reservoir eradication. We have followed infants and older children for >5-10 years with serial PBMC and plasma collection and have quantified HIV reservoir in a subset of children who started ART during the first year of life with viral suppression from these cohorts. We propose mechanistic virology/immunogy studies leveraging these unique repositories and to extend follow-up of these children to track longer term reservoir changes (>15 years since ART initiation in some children). Our overarching aim is to determine reservoir dynamics and decay using mathematical modeling and identify immune determinants of reservoir decline and size. This project will be led by multiple PIs (MPIs): Drs. John-Stewart and Lehman. With our combined expertise in pediatric HIV molecular epidemiology (John-Stewart, Wamalwa) virology (Lehman, Overbaugh), immunology (Slyker, Blish) and modeling (Holte, Matsen) we propose to model longitudinal reservoir dynamics, and determine effects of infant timing of HIV acquisition, ART timing, and the influence of infant immune activation, ADCC, and NK population characteristics on reservoir decline and size. These studies will provide novel data on reservoir dynamics during infancy and early childhood from sub Saharan Africa and will elucidate potential influence of immune activation, ADCC, and natural killer phenotype in reservoir containment, and ultimately inform intervention strategies for improved long-term management and reservoir control in HIV infected children.